The oxidative degradation of arginine into citrulline and nitric oxide by Nitric Oxide Synthase has generated a spectacular amount of world-wide research interest in the last several years. Nitric oxide is a thermodynamically unstable, reactive diatomic free radical and is not surprisingly, cytotoxic. Of perhaps greater interest, is that depending on the type of tissue where it is generated, nitric oxide has a number of diverse biological functions, such as regulation of blood pressure through vasodilation and neuronal signal transmission by stimulation of guanylyl cyclase. Three isoforms of Nitric Oxide Synthase have been isolated. Two of these, bNOS (brain) and eNOS (endothelial), are constitutive and dependent on calcium/calmodulin. The third, found in macrophages (iNOS), is inducible and calcium/calmodulin independent. In order to study the role nitric oxide in a number of pathological states, this work focuses on the discovery and development of inhibitors of Nitric Oxide Synthase that can be used for (in vivo) imaging by positron emission tomography. Two avenues of exploration have been underway during the past year. The more general of these has been the development of compounds which will inhibit any of the isoforms of the enzyme. Since none of the known NOS inhibitors has shown suitability for neuroimaging, due to poor brain penetration, a more specific avenue of research has been development of compounds which will cross the blood- brain barrier. To date, eleven potential ligands have been synthesized and are currently being evaluated for biological activity. These data are forthcoming.